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  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/04—Ortho-condensed systems
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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  • A61P5/00—Drugs for disorders of the endocrine system
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

• Described herein are compounds that are somatostatin modulators, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders that would benefit from modulating somatostatin activity.
• Somatostatin is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G-protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones.
• Six subtype somatostatin receptor proteins have been identified (SSTR1, SSTR2a, SSTR2b, SSTR3, SSTR4, SSTR5) and are encoded by five different somatostatin receptor genes. Modulation of a particular subtype somatostatin receptor or combination thereof, is attractive for the treatment of conditions, diseases, or disorders that would benefit from modulating somatostatin activity.
• Compounds described herein are somatostatin modulator compounds. In some embodiments, compounds described herein modulate one or more of the subtype somatostatin receptor proteins. In some embodiments, compounds described herein modulate one subtype somatostatin receptor. In some embodiments, compounds described herein modulate SSTR2 somatostatin receptor. Somatostatin peptide analogs, such as octreotide and pasireotide, formulated as depot injections, are routinely used to normalize hormone levels for the treatment of Growth Hormone (GH) secreting adenomas, pancreatic neuroendocrine tumors, and carcinoid tumors.
• GH Growth Hormone
• R 2 is hydrogen, substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci- C 4 fluoroalkyl, substituted or unsubstituted Ci-C 4 heteroalkyl, or substituted or unsubstituted C3-C 6 cycloalkyl;
• R 3 is hydrogen, substituted or unsubstituted Ci-C alkyl, substituted or unsubstituted Ci- C fluoroalkyl, substituted or unsubstituted Ci-C heteroalkyl, or substituted or unsubstituted C3-C 6 cycloalkyl;
• R 2 and R 3 are taken together with the N atom to which they are attached to form a substituted or unsubstituted 4-membered, substituted or unsubstituted 5-membered or substituted or unsubstituted 6-membered N-containing heterocyclic ring;
• R 5 is hydrogen, substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci- C 4 fluoroalkyl, substituted or unsubstituted C 2 -C 4 alkenyl, or substituted or unsubstituted C3-C 6 cycloalkyl;
• R 6 is substituted or unsubstituted Ci-C alkyl, substituted or unsubstituted Ci- C 4 fluoroalkyl, substituted or unsubstituted C 2 -C 4 alkenyl, substituted or
• R 7 is -CN
• each R 8 and R 9 is independently hydrogen, halogen, substituted or unsubstituted Ci- C 4 alkyl, substituted or unsubstituted Ci-C 4 fluoroalkyl, substituted or unsubstituted Ci-C 6 heteroalkyl, -CN, -OH, or substituted or unsubstituted Ci-C 4 alkoxy;
• X 1 is N or C-R 10 ;
• R 10 is hydrogen, F, Cl, Br, -CN, -N(R 15 ) 2 , substituted or unsubstituted Ci-C alkyl, substituted or unsubstituted Ci-C 4 alkoxy, substituted or unsubstituted Ci- C 4 fluoroalkyl, substituted or unsubstituted Ci-C 4 fluoroalkoxy, substituted or unsubstituted Ci-C heteroalkyl, or substituted or unsubstituted C 3 -C 6 cycloalkyl;
• R 12 is hydrogen, or substituted or unsubstituted Ci-C 6 alkyl
• Ci-C 6 alkyl substituted or unsubstituted Ci-C 6 fluoroalkyl, or substituted or unsubstituted Ci-C 6 heteroalkyl;
• R 12 and R 13 are taken together with the intervening atoms to which they are attached to form a substituted or unsubstituted N-containing heterocyclic ring;
• R 12 and R 16 are taken together with the intervening atoms to which they are attached to form a substituted or unsubstituted N-containing heterocyclic ring;
• each R 14 is independently selected from substituted or unsubstituted Ci-C 6 alkyl
• Ci-C 6 heteroalkyl substituted or unsubstituted C 3 - C 7 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl;
• each R 15 is independently selected from hydrogen, substituted or unsubstituted Ci- C 6 alkyl, substituted or unsubstituted Ci-C 6 heteroalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl;
• each R 16 is independently selected from hydrogen, substituted or unsubstituted Ci- C 6 alkyl, substituted or unsubstituted Ci-C 6 heteroalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl;
• the compound of Formula (I) has the structure of Formula (la), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, or individual enantiomer thereof:
• the compound of Formula (I) has the structure of Formula (lb), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, or individual enantiomer thereof:
• the compound of Formula (I) has the following structure of Formula (Ic), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, or individual enantiomer thereof:
• R 2 is hydrogen or substituted or unsubstituted Ci-C 4 alkyl
• R 3 is hydrogen or substituted or unsubstituted Ci-C 4 alkyl
• R 2 and R 3 are taken together with the N atom to which they are attached to form a substituted or unsubstituted 5-membered or substituted or unsubstituted 6- membered N-containing heterocyclic ring;
• R 5 is hydrogen or substituted or unsubstituted Ci-C alkyl
• R 6 is substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci- C 4 fluoroalkyl, substituted or unsubstituted C 2 -C 4 alkenyl, substituted or
• each R 8 and R 9 is independently hydrogen, halogen, substituted or unsubstituted Ci- C alkyl, substituted or unsubstituted Ci-C fluoroalkyl, substituted or unsubstituted Ci-C 6 heteroalkyl, -CN, -OH, or substituted or unsubstituted Ci-C 4 alkoxy;
• each R 15 is independently selected from hydrogen, substituted or unsubstituted Ci- C 6 alkyl, substituted or unsubstituted Ci-C 6 heteroalkyl, substituted or unsubstituted C3-C 7 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl;
• R 5 is hydrogen, substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci-C 4 fluoroalkyl, substituted or unsubstituted C 2 -C alkenyl, or substituted or unsubstituted C3-C 6 cycloalkyl;
• each R 8 and R 9 is independently hydrogen, halogen, substituted or unsubstituted Ci- C 4 alkyl, substituted or unsubstituted Ci-C 4 fluoroalkyl, substituted or unsubstituted Ci-C 6 heteroalkyl, -CN, -OH, or substituted or unsubstituted Ci-C 4 alkoxy;
• X 1 is N or C-R 10 ;
• R 10 is hydrogen, F, Cl, Br, -CN, -N(R 15 ) 2 , substituted or unsubstituted Ci-C alkyl, substituted or unsubstituted Ci-C 4 alkoxy, substituted or unsubstituted Ci- C 4 fluoroalkyl, substituted or unsubstituted Ci-C 4 fluoroalkoxy, substituted or unsubstituted Ci-C heteroalkyl, or substituted or unsubstituted C 3 -C 6 cycloalkyl;
• R 12 is hydrogen, or substituted or unsubstituted Ci-C 6 alkyl
• Ci-C 6 alkyl substituted or unsubstituted Ci-C 6 fluoroalkyl, or substituted or unsubstituted Ci-C 6 heteroalkyl;
• R 12 and R 13 are taken together with the intervening atoms to which they are
• R 12 and R 16 are taken together with the intervening atoms to which they are
• each R 14 is independently selected from substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted Ci-C 6 heteroalkyl, substituted or unsubstituted C 3 - C 7 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl;
• each R 15 is independently selected from hydrogen, substituted or unsubstituted Ci- C 6 alkyl, substituted or unsubstituted Ci-C 6 heteroalkyl, substituted or unsubstituted C3-C 7 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl;
• each R 16 is independently selected from hydrogen, substituted or unsubstituted Ci- C 6 alkyl, substituted or unsubstituted Ci-C 6 heteroalkyl, substituted or unsubstituted C3-C 7 cycloalkyl, substituted or unsubstituted monocyclic C2-C 6 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl;
• the compound of Formula (II) has the structure of Formula (Ila), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,
• the compound of Formula (II) has the structure of Formula (lib), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,
• the compound of Formula (II) has the following structure of Formula (He), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, or individual enantiomer thereof:
• R 5 is hydrogen or substituted or unsubstituted Ci-C 4 alkyl
• each R 6 and R 7 is independently halogen, substituted or unsubstituted Ci-C 4 alkyl
• each R 8 and R 9 is independently hydrogen, halogen, substituted or unsubstituted Ci- C 4 alkyl, substituted or unsubstituted Ci-C 4 fluoroalkyl, substituted or unsubstituted Ci-C 6 heteroalkyl, -CN, -OH, or substituted or unsubstituted Ci-C alkoxy;
• each R 15 is independently selected from hydrogen, substituted or unsubstituted Ci- C 6 alkyl, substituted or unsubstituted Ci-C 6 heteroalkyl, substituted or unsubstituted C3-C 7 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl;
• R 1 is -NR 2 R 3 , -OR 2 , or R 4 ;
• R 2 is hydrogen, substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci-C4fluoroalkyl, substituted or unsubstituted Ci-C 4 heteroalkyl, or substituted or unsubstituted C3-C 6 cycloalkyl;
• R 3 is hydrogen, substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci-C 4 fluoroalkyl, substituted or unsubstituted Ci-C 4 heteroalkyl, or substituted or unsubstituted C3-C 6 cycloalkyl;
• R 2 and R 3 are taken together with the N atom to which they are attached to form a substituted or unsubstituted 4-membered, substituted or unsubstituted 5-membered or substituted or unsubstituted 6-membered N-containing heterocyclic ring;
• R 4 is F, Cl, Br, -CN, substituted or unsubstituted Ci-C 4 alkyl, substituted or
• R 5 is hydrogen, substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci-C 4 fluoroalkyl, substituted or unsubstituted C 2 -C 4 alkenyl, or substituted or unsubstituted C3-C 6 cycloalkyl;
• each R 8 and R 9 is independently hydrogen, halogen, substituted or unsubstituted Ci- C 4 alkyl, substituted or unsubstituted Ci-C 4 fluoroalkyl, substituted or unsubstituted Ci-C 6 heteroalkyl, -CN, -OH, or substituted or unsubstituted Ci-C 4 alkoxy;
• X 1 is N or C-R 10 ;
• R 10 is hydrogen, F, Cl, Br, -CN, -N(R 15 ) 2 , substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci-C 4 alkoxy, substituted or unsubstituted Ci- C 4 fluoroalkyl, substituted or unsubstituted Ci-C 4 fluoroalkoxy, substituted or unsubstituted Ci-C 4 heteroalkyl, or substituted or unsubstituted C3-C 6 cycloalkyl;
• R 11 is hydrogen or substituted or unsubstituted Ci-C 6 alkyl;
• each R 15 is independently selected from hydrogen, substituted or unsubstituted Ci- C 6 alkyl, substituted or unsubstituted Ci-C 6 heteroalkyl, substituted or unsubstituted C3-C 7 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 6 heterocycl oal kyl , substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl;
• the compound of Formula (III) has the following structure of Formula (Ilia), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, or individual enantiomer thereof:
• R 1 is -NR 2 R 3 , -OR 2 , F, Cl, Br, -CN, Ci-C 4 alkyl, or Ci-C 4 fluoroalkyl;
• R 2 is hydrogen or substituted or unsubstituted Ci-C alkyl
• R 3 is hydrogen or substituted or unsubstituted Ci-C alkyl
• R 2 and R 3 are taken together with the N atom to which they are attached to form a substituted or unsubstituted 5-membered or substituted or unsubstituted 6- membered N-containing heterocyclic ring;
• R 5 is hydrogen or substituted or unsubstituted Ci-C alkyl
• R 11 is hydrogen or substituted or unsubstituted Ci-C 4 alkyl
• each R 15 is independently selected from hydrogen, substituted or unsubstituted Ci- C 6 alkyl, substituted or unsubstituted Ci-C 6 heteroalkyl, substituted or unsubstituted C3-C 7 cycloalkyl, substituted or unsubstituted monocyclic C -C f rieterocycl oal kyl , substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl;
• a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, or solvate thereof, and at least one pharmaceutically acceptable excipient.
• the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration.
• the pharmaceutical composition is formulated for administration to a mammal by oral administration.
• the pharmaceutical composition is in the form of a tablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion, a solution, an emulsion, an ointment, or a lotion.
• the pharmaceutical composition is in the form of a tablet, a pill, or a capsule.
• Also described herein is a method of treating a disease or condition in a mammal that would benefit from the modulation of somatostatin receptor activity comprising administering a small molecule non-peptidyl compound, or pharmaceutically acceptable salt, or solvate thereof, to the mammal in need thereof.
• the small molecule non-peptidyl compound is orally administered.
• the small molecule non-peptidyl compound is a compound as described herein, or a pharmaceutically acceptable salt or solvate thereof.
• the small molecule non-peptidyl compound is a SSTR2 modulator as described herein, or a pharmaceutically acceptable salt or solvate thereof.
• the disease or condition is acromegaly, a neuroendocrine tumor, an ophthalmic disease or condition, neuropathy, nephropathy, a respiratory disease or condition, cancer, pain, a neurodegenerative disease or condition, an inflammatory disease or condition, a psychiatric disease or condition, or combinations thereof.
• the effective amount of the compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by inhalation; and/or (e) administered by nasal administration; or and/or (f) administered by injection to the mammal; and/or (g) administered topically to the mammal; and/or (h) administered by ophthalmic administration; and/or (i) administered rectally to the mammal; and/or (j) administered non-systemically or locally to the mammal.
• any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which the compound is administered once a day to the mammal or the compound is administered to the mammal multiple times over the span of one day.
• the compound is administered on a continuous dosing schedule.
• the compound is administered on a continuous daily dosing schedule.
• the mammal is a human.
• compounds provided herein are orally administered to a human.
• Articles of manufacture which include packaging material, a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, within the packaging material, and a label that indicates that the compound or composition, or pharmaceutically acceptable salt, tautomers, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or
• Somatostatin also known as somatotropin release inhibiting factor (SRIF) was initially isolated as a l4-amino acid peptide from ovine hypothalamii (Brazeau et al ., Science 179, 77-79, 1973).
• Somatotropin release inhibiting factor SST
• SST Somatotropin release inhibiting factor
• An /V-terminal extended 28-amino acid peptide with similar biological activity to l4-amino acid somatostatin was subsequently isolated (Pradayrol et, al ., FEBS Letters, 109, 55-58, 1980; Esch et al, Proc. Natl. Acad. Sci. USA , 77, 6827-6831, 1980).
• SST is a regulatory peptide produced by several cell types in response to other neuropeptides, neurotransmitters, hormones, cytokines, and growth factors. SST acts through both endocrine and paracrine pathways to affect its target cells. Many of these effects are related to the inhibition of secretion of other hormones, most notably growth hormone (GH). They are produced by a wide variety of cell types in the central nervous system (CNS) and gut and have multiple functions including modulation of secretion of growth hormone (GH), insulin, glucagon, as well as many other hormones that are anti-proliferative.
• GH growth hormone
• SSTR1 SSTR2a
• SSTR2b SSTR3, SSTR4, SSTR5
• SSTR5a SSTR2a
• SSTR2b SSTR3
• SSTR4a SSTR5a
• SSTR2a SSTR2a receptor
• any one of the somatostatin receptor subtypes it is possible to selectively modulate any one of the somatostatin receptor subtypes, or combination thereof. In some embodiments, selectively modulating any one of the somatostatin receptor subtypes relative to the other somatostatin receptor subtypes reduces unwanted side effects in a variety of clinical applications.
• selective modulation of SSTR2 activity mediates the inhibition of growth hormone (GH) release from the anterior pituitary and glucagon release from pancreas.
• GH growth hormone
• SSTR2 is also implicated in many other biological functions such as, but not limited to, cell proliferation, nociception, inflammation, and angiogenesis.
• a selective SSTR2 modulator is used in the treatment of acromegaly, neuroendocrine tumors, pain, neuropathies, nephropathies, and inflammation, as well as retinopathies resulting from aberrant blood vessel growth.
• a selective SSTR2 modulator is used in the treatment of arthritis, pain, cancer, inflammatory bowel disease, irritable bowel syndrome, Crohn’s disease, Cushing’s disease, acute lung injury, acute respiratory distress syndrome, and ophthalmic disorders such as age-related macular degeneration (AMD), diabetic retinopathy, diabetic macular edema, and Graves ophthalmology, among others.
• AMD age-related macular degeneration
• diabetic retinopathy diabetic macular edema
• Graves ophthalmology among others.
• compounds described herein are modulators of SSTR2. In some embodiments, compounds described herein selectively modulate the activity of SSTR2 relative to the other somatostatin receptors.
• compounds described here are amenable to oral
• somatostatin receptor modulators described herein have utility over a wide range of therapeutic applications.
• somatostatin receptor modulators described herein are used in the treatment of a variety of diseases or conditions such as, but not limited to acromegaly, neuroendocrine tumors, retinopathies and other ophthalmic disorders, neuropathy, nephropathy, respiratory diseases, cancers, pain, neurodegenerative diseases, inflammatory diseases, as well as psychiatric and
• somatostatin receptor modulators described herein are used in the treatment of acromegaly in a mammal.
• somatostatin receptor modulators described herein inhibit the secretion of various hormones and trophic factors in mammals.
• the compounds are used to suppress certain endocrine secretions, such as, but not limited to GH, insulin, glucagon and prolactin.
• endocrine secretions such as, but not limited to GH, insulin, glucagon and prolactin.
• the suppression of certain endocrine secretions is useful in the treatment of disorders such as acromegaly; endocrine tumors such as carcinoids,
• VIPomas insulinomas and glucagonomas
• diabetes and diabetes-related pathologies including retinopathy, neuropathy and nephropathy.
• somatostatin receptor modulators described herein are used to suppress exocrine secretions in the pancreas, stomach and intestines, for the treatment of disorders such as pancreatitis, fistulas, bleeding ulcers and diarrhea associated with such diseases as AIDS or cholera.
• disorders involving autocrine or paracrine secretions of trophic factors such as IGF-l which may be treated by administration of the compounds described herein include cancers of the breast, prostate, and lung (both small cell and non-small cell epidermoids), as well as hepatomas, neuroblastomas, colon and pancreatic adenocarcinomas (ductal type), chondrosarcomas, and melanomas, diabetic retinopathy, and atherosclerosis associated with vascular grafts and restenosis following angioplasty.
• trophic factors such as IGF-l (as well as some endocrine factors) which may be treated by administration of the compounds described herein include cancers of the breast, prostate, and lung (both small cell and non-small cell epidermoids), as well as hepatomas, neuroblastomas, colon and pancreatic adenocarcinomas (ductal type), chondrosarcomas, and melanomas, diabetic retinopathy, and at
• somatostatin receptor modulators described herein are used to suppress the mediators of neurogenic inflammation (e.g. substance P or the tachykinins), and may be used in the treatment of rheumatoid arthritis; psoriasis; topical inflammation such as is associated with sunburn, eczema, or other sources of itching; inflammatory bowel disease; irritable bowel syndrome; allergies, including asthma and other respiratory diseases
• the somatostatin receptor modulators described herein function as neuromodulators in the central nervous system and are useful in the treatment of
• Alzheimer's disease and other forms of dementia, pain, and headaches are associated with Alzheimer's disease and other forms of dementia, pain, and headaches. In some aspects
• somatostatin receptor modulators described herein provide cytoprotection in disorders involving the splanchnic blood flow, including cirrhosis and oesophagal varices.
• pharmaceutically acceptable salts, prodrugs, active metabolites and pharmaceutically acceptable solvates thereof are somatostatin receptor modulators.
• the compounds of Formula (I), Formula (II), or Formula (III), including pharmaceutically acceptable salts, prodrugs, active metabolites and pharmaceutically acceptable solvates thereof are SSTR2 modulators.
• the somatostatin receptor modulators are somatostatin receptor agonists.
• compounds described herein are at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 15 times, at least 20 times, at least 30 times, at least 40 times, at least 50 times, at least 100 times, at least 200 times more selective at modulating SSTR2 activity than SSTR4 receptor activity.
• the R 1 group of the compounds described herein confers selectivity for modulating SSTR2 activity.
• SSTR2 modulators have increased water solubility and reduced possibility to be BBB penetrable by increasing hydrogen bond donors.
• the R 1 group of the compounds described herein reduced liability associated BBB penetration.
• the R 1 group of the compounds herein described increased water solubility.
• R 1 group of the compounds herein described reduce metabolic instability in human liver microsomes.
• R 1 corresponds to -NR 2 R 3 of Formula (I).
• R 2 is hydrogen, substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci- C 4 fluoroalkyl, substituted or unsubstituted Ci-C 4 heteroalkyl, or substituted or unsubstituted C 3 -C 6 cycloalkyl;
• R 3 is hydrogen, substituted or unsubstituted Ci-C alkyl, substituted or unsubstituted Ci- C 4 fluoroalkyl, substituted or unsubstituted Ci-C 4 heteroalkyl, or substituted or unsubstituted C3-C 6 cycloalkyl;
• R 2 and R 3 are taken together with the N atom to which they are attached to form a substituted or unsubstituted 4-membered, substituted or unsubstituted 5-membered or substituted or unsubstituted 6-membered N-containing heterocyclic ring;
• R 5 is hydrogen, substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci- C fluoroalkyl, substituted or unsubstituted C 2 -C alkenyl, or substituted or unsubstituted C 3 -C 6 cycloalkyl;
• R 6 is substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci- C 4 fluoroalkyl, substituted or unsubstituted C 2 -C 4 alkenyl, substituted or
• R 7 is -CN; each R 8 and R 9 is independently hydrogen, halogen, substituted or unsubstituted Ci- C 4 alkyl, substituted or unsubstituted Ci-C 4 fluoroalkyl, substituted or unsubstituted Ci-C 6 heteroalkyl, -CN, -OH, or substituted or unsubstituted Ci-C alkoxy;
• X 1 is N or C-R 10 ;
• R 10 is hydrogen, F, Cl, Br, -CN, -N(R 15 ) 2 , substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci-C 4 alkoxy, substituted or unsubstituted Ci- C fluoroalkyl, substituted or unsubstituted Ci-C fluoroalkoxy, substituted or unsubstituted Ci-C heteroalkyl, or substituted or unsubstituted C 3 -C 6 cycloalkyl;
• R 12 is hydrogen, or substituted or unsubstituted Ci-C 6 alkyl
• Ci-C 6 alkyl substituted or unsubstituted Ci-C 6 fluoroalkyl, or substituted or unsubstituted Ci-C 6 heteroalkyl;
• R 12 and R 13 are taken together with the intervening atoms to which they are attached to form a substituted or unsubstituted N-containing heterocyclic ring;
• R 12 and R 16 are taken together with the intervening atoms to which they are attached to form a substituted or unsubstituted N-containing heterocyclic ring;
• each R 14 is independently selected from substituted or unsubstituted Ci-C 6 alkyl
• Ci-C 6 heteroalkyl substituted or unsubstituted C 3 - C 7 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl;
• each R 15 is independently selected from hydrogen, substituted or unsubstituted Ci- C 6 alkyl, substituted or unsubstituted Ci-C 6 heteroalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl;
• R 15 on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle; and R 16 is independently selected from hydrogen, substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted Ci-C 6 heteroalkyl, substituted or unsubstituted C 3 - C 7 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl; or two R 16 on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle.
• substituents are selected from among a subset of the listed alternatives.
• X is C-R 1 or N.
• X is C-R 1 .
• X is N.
• R 12 is hydrogen or substituted or unsubstituted Ci-C 6 alkyl. In some embodiments, R 12 is hydrogen. In some embodiments, R 12 is substituted or
• the compound of Formula (I) has the structure of Formula (la), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,
• the compound of Formula (I) has the structure of Formula (Ia-l), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, or individual enantiomer thereof:
• the compound of Formula (I) has the structure of Formula (lb), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,
• the compound of Formula (I) has the structure of Formula (Ib-l), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, or individual enantiomer thereof:
• R 2 is hydrogen, Ci-C 4 alkyl, Ci-C 4 fluoroalkyl, or C 3 - C 6 cycloalkyl
• R 3 is hydrogen, Ci-C 4 alkyl, Ci-C 4 fluoroalkyl, or C 3 -C 6 cycloalkyl
• R 2 and R 3 are taken together with the N atom to which they are attached to form a substituted or unsubstituted 5-membered or substituted or unsubstituted 6-membered N-containing heterocyclic ring.
• R 2 is hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -
• R 3 is hydrogen, -C3 ⁇ 4, -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , - CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -CH(CH 3 )(CH 2 CH 3 ), -C(CH 3 ) 3 , -CH 2 CH 2 OH, or -CH 2 CH 2 OCH 3 ;
• R 3 is hydrogen, -C3 ⁇ 4, -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , - CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -CH(CH 3 )(CH 2 CH 3 ), -C(CH 3 ) 3 , -CH 2 CH 2 OH, -
• R 2 and R 3 are taken together with the N atom to which they are attached to form a substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted
• R 2 is hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -
• R 3 is hydrogen, -C3 ⁇ 4, -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -CH 2 CF 3 , -
• R 2 and R 3 are taken together with the N atom to which they are attached to form substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl, or substituted or unsubstituted piperazinyl.
• R 2 is hydrogen, -C3 ⁇ 4, -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 , or -CH 2 CH 2 OCF 3 ;
• R 3 is hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 CF 3 , -CH 2 CH 2 OH, - CH 2 CH 2 OCH 3 , or -CH 2 CH 2 OCF 3 ; or R 2 and R 3 are taken together with the N atom to which they are attached to form substituted or unsubstituted pyrrolidinyl, substituted or
• R 2 is hydrogen, -CH 3 , -CH 2 CH 2 OH, - CH 2 CH 2 OCH 3 , or -CH 2 CH 2 OCF 3
• R 3 is hydrogen, -CH 3 , -CH 2 CF 3 , -CH 2 CH 2 OH, - CH 2 CH 2 OCH 3 , or -CH 2 CH 2 OCF 3
• R 2 and R 3 are taken together with the N atom to which they are attached to form substituted or unsubstituted pyrrolidinyl, substituted or
• R 2 is hydrogen or -CH 3 ; and R 3 is hydrogen or -CH 3 .
• R 5 is hydrogen, substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci-C 4 fluoroalkyl, or substituted or unsubstituted C 3 -C 6 cycloalkyl. In some embodiments, R 5 is hydrogen or substituted or unsubstituted Ci-C alkyl. In some embodiments, R 5 is hydrogen, -CH 3 , -CH 2 CH 3 , or -CH 2 CH 2 CH 3 . In some embodiments, R 5 is hydrogen.
• R 6 is substituted or unsubstituted Ci-C alkyl, substituted or unsubstituted Ci-C 4 fluoroalkyl, substituted or unsubstituted C 2 -C 4 alkenyl, substituted or unsubstituted C 2 - C 4 alkynyl, -CN, or -OR 15 .
• R 6 is -CH 3 , -CF 3 , -CN, -OCH 3 , or -OCF 3 . In some embodiments, R 6 is -CH 3 , -CN, -OCH 3 , or -OCF 3 . In some embodiments, R 6 is - OCH 3 .
• each R 8 and R 9 is independently hydrogen, halogen, Ci- C 4 alkyl, Ci-C 4 fluoroalkyl, or Ci-C 4 alkoxy. In some embodiments, each R 8 and R 9 is independently hydrogen, F, Cl, Br, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -
• each R 8 and R 9 is independently hydrogen, F, Cl, Br, -CH 3 , -CH 2 F, -CHF 2 , -CH 2 CF 3 , or -OCH 3 .
• each R 8 and R 9 is independently F, Cl, Br, -CH 3 , -CH 2 CH 3 , or -OCH 3 .
• each R 8 and R 9 is independently F, Cl, Br, -CH 3 , -CH 2 CH 3 , or -OCH 3 .
• each R 8 and R 9 is independently F, Cl, -CH 3 , or -OCH 3 .
• R 12 is hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , or - CH(CH 3 ) 2 ;
• R 12 is hydrogen, -CH 3 , or -CH 2 CH 3 ;
• R 12 is hydrogen, -CH 3 , or -CH 2 CH 3 ;
• R 13 is hydrogen, -OCH 3 , -OCH 2 CH 3 , or -OCF 3 ; or
• R 12 and R 13 are taken together with the intervening atoms to which they are attached to form a substituted or unsubstituted N- containing 6-membered heterocyclic ring; or
• R 12 and R 16 are taken together with the intervening atoms to which they are attached to form a substituted or unsubstituted morpholinyl.
• R 12 is hydrogen; and R 13 is hydrogen.
• the compound of Formula (I) has the structure of Formula (Ic), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,
• R 2 is hydrogen or substituted or unsubstituted Ci-C 4 alkyl
• R 3 is hydrogen or substituted or unsubstituted Ci-C 4 alkyl
• R 2 and R 3 are taken together with the N atom to which they are attached to form a substituted or unsubstituted 5-membered or substituted or unsubstituted 6- membered N-containing heterocyclic ring;
• R 5 is hydrogen or substituted or unsubstituted Ci-C 4 alkyl
• R 6 is substituted or unsubstituted Ci-C alkyl, substituted or unsubstituted Ci- C fluoroalkyl, substituted or unsubstituted C 2 -C alkenyl, substituted or
• each R 8 and R 9 is independently hydrogen, halogen, substituted or unsubstituted Ci- C 4 alkyl, substituted or unsubstituted Ci-C 4 fluoroalkyl, substituted or unsubstituted Ci-C 6 heteroalkyl, -CN, -OH, or substituted or unsubstituted Ci-C alkoxy;
• each R 15 is independently selected from hydrogen, substituted or unsubstituted Ci- C 6 alkyl, substituted or unsubstituted Ci-C 6 heteroalkyl, substituted or unsubstituted C3-C 7 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl;
• R 2 is hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 , or -CH 2 CH 2 OCF 3 ;
• R 3 is hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -CH 2 CH 2 OH, - CH 2 CH 2 OCH 3 , or -CH 2 CH 2 OCF 3 ; or R 2 and R 3 are taken together with the N atom to which they are attached to form substituted or unsubstituted pyrrolidinyl, substituted or
• R 5 is hydrogen, -CH 3 , -CH 2 CH 3 , or -CH 2 CH 2 CH 3 .
• R 2 is hydrogen, -CH 3 , - CH 2 CH 3 , -CH 2 CH 2 CH 3 , or -CH(CH 3 ) 2
• R 3 is hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , or - CH(CH 3 ) 2
• R 2 and R 3 are taken together with the N atom to which they are attached to form substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl, or substituted or unsubstituted piperazinyl
• R 5 is hydrogen,
• R 6 is substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci-C 4 fluoroalkyl, substituted or unsubstituted C 2 -C 4 alkenyl, substituted or unsubstituted C 2 -C alkynyl, -CN, or -OR 15 ; and each R 8 and R 9 is independently hydrogen, halogen, Ci-C alkyl, Ci-C fluoroalkyl, or Ci-C alkoxy.
• R 6 is - CH 3 , -CF 3 , -CN, -OCH 3 , or -OCF 3 ; and each R 8 and R 9 is independently F, Cl, Br, -CH 3 , - CH 2 CH 3 , or -OCH 3 .
• R 6 is -CH 3 , -CN, -OCH 3 , or -OCF 3 ; and each R 8 and R 9 is independently F, Cl, -CH 3 , or -OCH 3 ;
• the compound of Formula (I) has the structure of Formula (Ic-l), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, or individual enantiomer thereof:
• the compound of Formula (I) has the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, or individual enantiomer thereof:
• R 2 , R 3 , R 8 , and R 9 are as described in Table 1. [0056] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.
• the compound of Formula (I) could have the structure of Formula (Id) or (Ie).
• Formula (Id) and Formula (Ie) are tautomers.
• Formula (la) and Formula (Ia-l) are tautomers
• Formula (lb) and Formula (Ib-l) are tautomers
• Formula (Ic) and Formula (Ic-l) are tautomers.
• Exemplary compounds described herein include the compounds described in the following Table 1.
• provided herein is a pharmaceutically acceptable salt of a compound that is described in Table 1.
• R 5 is hydrogen, substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci-C 4 fluoroalkyl, substituted or unsubstituted C 2 -C 4 alkenyl, or substituted or unsubstituted C3-C 6 cycloalkyl;
• each R 8 and R 9 is independently hydrogen, halogen, substituted or unsubstituted Ci- C 4 alkyl, substituted or unsubstituted Ci-C 4 fluoroalkyl, substituted or unsubstituted Ci-C 6 heteroalkyl, -CN, -OH, or substituted or unsubstituted Ci-C 4 alkoxy;
• X 1 is N or C-R 10 ;
• R 10 is hydrogen, F, Cl, Br, -CN, -N(R 15 ) 2 , substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci-C 4 alkoxy, substituted or unsubstituted Ci- C fluoroalkyl, substituted or unsubstituted Ci-C fluoroalkoxy, substituted or unsubstituted Ci-C heteroalkyl, or substituted or unsubstituted C 3 -C 6 cycloalkyl;
• R 12 is hydrogen, or substituted or unsubstituted Ci-C 6 alkyl;
• Ci-C 6 alkyl substituted or unsubstituted Ci-C 6 fluoroalkyl, or substituted or unsubstituted Ci-C 6 heteroalkyl;
• R 12 and R 13 are taken together with the intervening atoms to which they are
• R 12 and R 16 are taken together with the intervening atoms to which they are
• each R 14 is independently selected from substituted or unsubstituted Ci-C 6 alkyl, substituted or unsubstituted Ci-C 6 heteroalkyl, substituted or unsubstituted C 3 - C 7 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl;
• each R 15 is independently selected from hydrogen, substituted or unsubstituted Ci- C 6 alkyl, substituted or unsubstituted Ci-C 6 heteroalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl;
• each R 16 is independently selected from hydrogen, substituted or unsubstituted Ci- C 6 alkyl, substituted or unsubstituted Ci-C 6 heteroalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl;
• the compound of Formula (II) has the structure of Formula (Ila), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,
• the compound of Formula (II) has the structure of Formula (lib), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,
• each R 15 is independently hydrogen or Ci-C 4 alkyl.
• R 5 is hydrogen, substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci-C fluoroalkyl, or substituted or unsubstituted C 3 -C 6 cycloalkyl.
• R 5 is hydrogen or substituted or unsubstituted Ci-C alkyl. In some embodiments, R 5 is hydrogen, -CH 3 , -CH 2 CH 3 , or -CH 2 CH 2 CH 3 . In some embodiments, R 5 is hydrogen.
• each R 6 and R 7 is independently substituted or unsubstituted Ci-C 4 alkyl, substituted or
• each R 6 and R 7 is independently F, Cl, -CH 3 , -CF 3 , -CN, -OCH 3 , or -OCF 3 .
• each R 6 and R 7 is independently F, Cl, -CN, or -OCH 3 . In some embodiments, each R 6 and R 7 is independently F, Cl, Br, -CH 3 , -CF 3 , -CN, -OH, -OCH 3 , or - OCF 3 . In some embodiments, each R 6 and R 7 is independently F, Cl, -CN or -OCH 3 .
• each R 8 and R 9 is independently halogen, Ci-C 4 alkyl, Ci- C fluoroalkyl, or Ci-C alkoxy.
• each R 8 and R 9 is independently F, Cl, Br, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , - CH(CH 3 )(CH 2 CH 3 ), -C(CH 3 ) 3 , -CH 2 F, -CHF 2 , -CH 2 CF 3 , -OCH 3 , or -OCH 2 CH 3 .
• each R 8 and R 9 is independently hydrogen, F, Cl, Br, -CH 3 , -OCH 3 , -CH 2 F, - CHF 2 , or -CH 2 CF 3 . In some embodiments, each R 8 and R 9 is independently F, Cl, Br, -CH 3 , or -OCH 3 . In some embodiments, each R 8 and R 9 is independently F, Cl, -CH 3 , or -OCH 3 .
• R 12 is hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , or - CH(CH 3 ) 2 ;
• R 12 is hydrogen, -CH 3 , or -CH 2 CH 3 ;
• R 12 is hydrogen, -CH 3 , or -CH 2 CH 3 ;
• R 13 is hydrogen, -OCH 3 , -OCH 2 CH 3 , or -OCF 3 ; or R 12 and R 13 are taken together with the intervening atoms to which they are attached to form a substituted or unsubstituted N-containing 6-membered
• R 12 and R 16 are taken together with the intervening atoms to which they are attached to form a substituted or unsubstituted morpholinyl.
• R 12 is hydrogen; and R 13 is hydrogen
• the compound of Formula (II) has the structure of Formula (lie), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,
• R 5 is hydrogen or substituted or unsubstituted Ci-C 4 alkyl
• each R 6 and R 7 is independently halogen, substituted or unsubstituted Ci-C 4 alkyl
• each R 15 is independently selected from hydrogen, substituted or unsubstituted Ci- C 6 alkyl, substituted or unsubstituted Ci-C 6 heteroalkyl, substituted or unsubstituted C3-C 7 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl;
• R 1 is -C0 2 CH 3 , or - CO 2 CH 2 CH 3 .
• each R 6 and R 7 is independently halogen, substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci-C 4 fluoroalkyl, substituted or unsubstituted C 2 -C 4 alkenyl, substituted or unsubstituted C 2 -C 4 alkynyl, -CN, or -OR 15 ; and each R 8 and R 9 is independently hydrogen, halogen, Ci-C 4 alkyl, Ci-C 4 fluoroalkyl, or Ci- C alkoxy.
• each R 6 and R 7 is independently F, Cl, Br, -CH 3 , -CF 3 , -CN, -OH, -OCH 3 , or -OCF 3 . In some embodiments, each R 6 and R 7 is independently F, Cl, -CN, or -OCH 3 . In some embodiments, each R 8 and R 9 is independently hydrogen, halogen, Ci- C 4 alkyl, Ci-C 4 fluoroalkyl, or Ci-C 4 alkoxy.
• each R 8 and R 9 is independently hydrogen, F, Cl, Br, -C3 ⁇ 4, -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , - CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -CH(CH 3 )(CH 2 CH 3 ), -C(CH 3 ) 3 , -CH 2 F, -CHF 2 , -CH 2 CF 3 , -OCH 3 , or -OCH 2 CH 3 .
• each R 8 and R 9 is independently hydrogen, F, Cl, -CH 3 , or -OCH 3 .
• the compound of Formula (II) has the structure of Formula (lie- 1 ), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, or individual enantiomer thereof:
• the compound of Formula (II) has the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, or individual enantiomer thereof:
• R 1 is as described in Table 2.
• the compound of Formula (II) could have the structure of Formula (lid) or (He).
• Formula (lid) and Formula (He) are tautomers.
• Formula (lid) and Formula (He) should be considered as identical structures even their names could be different:
• Exemplary compounds described herein include the compounds described in the following Table 2.
• provided herein is a pharmaceutically acceptable salt of a compound that is described in Table 2.
• R 1 is -NR 2 R 3 , -OR 2 , or R 4 ;
• R 2 is hydrogen, substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci-C 4 fluoroalkyl, substituted or unsubstituted Ci-C heteroalkyl, or substituted or unsubstituted C3-C 6 cycloalkyl;
• R 3 is hydrogen, substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci-C fluoroalkyl, substituted or unsubstituted Ci-C heteroalkyl, or substituted or unsubstituted C 3 -C 6 cycloalkyl;
• R 2 and R 3 are taken together with the N atom to which they are attached to form a substituted or unsubstituted 4-membered, substituted or unsubstituted 5-membered or substituted or unsubstituted 6-membered N-containing heterocyclic ring;
• R 4 is F, Cl, Br, -CN, substituted or unsubstituted Ci-C alkyl, substituted or
• R 5 is hydrogen, substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci-C 4 fluoroalkyl, substituted or unsubstituted C 2 -C 4 alkenyl, or substituted or unsubstituted C 3 -C 6 cycloalkyl;
• each R 8 and R 9 is independently hydrogen, halogen, substituted or unsubstituted Ci- C alkyl, substituted or unsubstituted Ci-C fluoroalkyl, substituted or unsubstituted Ci-C 6 heteroalkyl, -CN, -OH, or substituted or unsubstituted Ci-C alkoxy;
• X 1 is N or C-R 10 ;
• R 10 is hydrogen, F, Cl, Br, -CN, -N(R 15 ) 2 , substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci-C alkoxy, substituted or unsubstituted Ci- C fluoroalkyl, substituted or unsubstituted Ci-C fluoroalkoxy, substituted or unsubstituted Ci-C heteroalkyl, or substituted or unsubstituted C 3 -C 6 cycloalkyl;
• R 11 is hydrogen or substituted or unsubstituted Ci-C 6 alkyl
• each R 15 is independently selected from hydrogen, substituted or unsubstituted Ci- C 6 alkyl, substituted or unsubstituted Ci-C 6 heteroalkyl, substituted or unsubstituted C3-C 7 cycloalkyl, substituted or unsubstituted monocyclic C -C f rieterocycl oal kyl , substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl;
• R 1 is -NR 2 R 3 .
• R 2 is hydrogen, Ci- C 4 alkyl, Ci-C 4 fluoroalkyl, Ci-C 4 heteroalkyl, or C3-C 6 cycloalkyl
• R 3 is hydrogen, Ci-C 4 alkyl, Ci-C fluoroalkyl, Ci-C heteroalkyl, or C3-C 6 cycloalkyl
• R 2 and R 3 are taken together with the N atom to which they are attached to form a substituted or unsubstituted 4-membered, substituted or unsubstituted 5-membered or substituted or unsubstituted 6-membered N- containing heterocyclic ring.
• R 2 is hydrogen, -CH 3 , -CH 2 CH 3 , - CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -CH(CH 3 )(CH 2 CH 3 ), - C(CH 3 ) 3 , -CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 , or -CH 2 CN;
• R 3 is hydrogen, -C3 ⁇ 4, -CH 2 CH 3 , - CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -CH(CH 3 )(CH 2 CH 3 ), - C(CH 3 ) 3 , -CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 , -CH 2 CN, or -CH 2 CF 3 ; or R 2
• R 3 is hydrogen. In some embodiments, R 2 is -CH 3 .
• R 1 is -OR 2 .
• R 2 is hydrogen, -CH 3 , -
• R 4 is F, Cl, Br, -CN, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , - CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -CH(CH 3 )(CH 2 CH 3 ), -C(CH 3 ) 3 , -CH 2 F, - CHF 2 , -CF 3 , or -CH 2 CF 3 ;
• R 1 is -NR 2 R 3 , -OR 2 , F, Cl, Br, -CN, Ci-C 4 alkyl, or Ci- C 4 fluoroalkyl.
• R 5 is hydrogen or substituted or unsubstituted Ci-C 4 alkyl. In some embodiments, R 5 is hydrogen.
• each R 6 and R 7 is independently F, Cl, Br, -CH 3 , -CF 3 , -CN, -OH, -OCH 3 , or -OCF 3 . In some embodiments, each R 6 and R 7 is independently F, Cl, -CN, or -OCH 3 .
• each R 8 and R 9 is independently hydrogen, halogen, Ci- C alkyl, Ci-C fluoroalkyl, or Ci-C alkoxy.
• each R 8 and R 9 is independently hydrogen, F, Cl, Br, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , - CH 2 CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -CH(CH 3 )(CH 2 CH 3 ), -C(C3 ⁇ 4) 3 , -CH 2 F, -CHF 2 , -CH 2 CF 3 , -OCH 3 , or -OCH 2 CH 3 .
• each R 8 and R 9 is independently hydrogen, F, Cl, -CH 3 , or -OCH 3 .
• R 11 is hydrogen or Ci-C alkyl. In some embodiments, R 11 is hydrogen.
• the compound of Formula (III) has the structure of Formula (Ilia), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate,
• R 1 is -NR 2 R 3 , -OR 2 , F, Cl, Br, -CN, C 1 -C 4 alkyl, or Ci-C 4 fluoroalkyl;
• R 2 is hydrogen or substituted or unsubstituted Ci-C 4 alkyl
• R 3 is hydrogen or substituted or unsubstituted Ci-C 4 alkyl
• R 2 and R 3 are taken together with the N atom to which they are attached to form a substituted or unsubstituted 5-membered or substituted or unsubstituted 6- membered N-containing heterocyclic ring;
• R 5 is hydrogen or substituted or unsubstituted Ci-C 4 alkyl
• each R 8 and R 9 is independently hydrogen, halogen, substituted or unsubstituted Ci- C 4 alkyl, substituted or unsubstituted Ci-C 4 fluoroalkyl, substituted or unsubstituted Ci-C 6 heteroalkyl, -CN, -OH, or substituted or unsubstituted Ci-C 4 alkoxy;
• R 11 is hydrogen or substituted or unsubstituted Ci-C alkyl
• each R 15 is independently selected from hydrogen, substituted or unsubstituted Ci- C 6 alkyl, substituted or unsubstituted Ci-C 6 heteroalkyl, substituted or unsubstituted C3-C 7 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl;
• R 2 is hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 OH, -CH 2 CH 2 OCH 3 , or -CH 2 CH 2 OCF 3 ;
• R 3 is hydrogen, -CH 3 , CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 F, -CHF 2 , -CF 3J -CH 2 CF 3 , -CH 2 CH 2 OH,
• R 2 and R 3 are taken together with the N atom to which they are attached to form substituted or unsubstituted pyrrolidinyl, substituted or
• R 5 is hydrogen, -CH 3 , -CH 2 CH 3 , or -CH 2 CH 2 CH 3 .
• R 2 is hydrogen, -CH 3 , -
• R 3 is hydrogen, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , or -CH(CH 3 ) 2 ;
• R 2 and R 3 are taken together with the N atom to which they are attached to form substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl, or substituted or unsubstituted piperazinyl; and
• R 5 is hydrogen, -CH 3 , -CH 2 CH 3 , or - CH 2 CH 2 CH 3 .
• R 2 is hydrogen or -CH 3 ;
• R 3 is hydrogen; and
• R 5 is hydrogen.
• each R 6 and R 7 is independently halogen, substituted or unsubstituted Ci-C 4 alkyl, substituted or unsubstituted Ci-C4fluoroalkyl, substituted or unsubstituted C 2 -C 4 alkenyl, substituted or unsubstituted C 2 -C 4 alkynyl, -CN, or -OR 15 ; and each R 8 and R 9 is independently hydrogen, halogen, Ci-C 4 alkyl, Ci-C 4 fluoroalkyl, or Ci- C 4 alkoxy.
• each R 6 and R 7 is independently F, Cl, -CH 3 , -CF 3 , -CN, -OCH 3 , or -OCF 3 ; and each R 8 and R 9 is independently hydrogen, F, Cl, Br, -CH 3 , or -OCH 3 .
• each R 6 and R 7 is independently F, Cl, -CH 3 , -CN, -OCH 3 , or -OCF 3 ; and each R 8 and R 9 is independently hydrogen, F, Cl, -CH 3 , or -OCH 3
• the compound of Formula (III) has the structure of Formula (Illa-l), or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, or individual enantiomer thereof:
• the compound of Formula (III) has the following structure, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, diastereomeric mixture, or individual enantiomer thereof:
• R a , R 1 , R 8 , and R 9 are as described in Table 3.
• the compound of Formula (III) could have the structure of Formula (Illb) or (IIIc).
• Formula (Illb) and Formula (IIIc) are tautomers.
• Formula (Illb) and Formula (IIIc) should be considered as identical structures even their names could be different:
• Exemplary compounds described herein include the compounds described in the following Table 3.
• 3-1 4-[(4aS,8aS)-octahydro-lH-pyrido[3,4-b][l,4]oxazin-6-yl]-3-(4,6-difluoro-lH-l,3- benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-2-amine;
• 3-4 4-[(4aS,8aS)-octahydro-lH-pyrido[3,4-b][l,4]oxazin-6-yl]-3-(4,6-difluoro-lH-l,3- benzodiazol-2-yl)-5-(3-fluoro-5-methoxyphenyl)pyridin-2-amine;
• 3-13 4-[(4aS,8aS)-octahydro-lH-pyrido[3,4-b][l,4]oxazin-6-yl]-5-(3-chloro-5- fluorophenyl)-3-(6-fluoro-4-methoxy-lH-l,3-benzodiazol-2-yl)-N-methylpyridin-2-amine; 3-14: 4-[(4aS,8aS)-octahydro-lH-pyrido[3,4-b][l,4]oxazin-6-yl]-3-(6-fluoro-4-methoxy-lH-
• provided herein is a pharmaceutically acceptable salt of a compound that is described in Table 3.
• compounds described herein are in the form of pharmaceutically acceptable salts.
• active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure.
• the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the
• “Pharmaceutically acceptable,” as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
• pharmaceutically acceptable salt refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation.
• Pharmaceutical salts typically are more soluble and more rapidly soluble in stomach and intestinal juices than non ionic species and so are useful in solid dosage forms. Furthermore, because their solubility often is a function of pH, selective dissolution in one or another part of the digestive tract is possible and this capability can be manipulated as one aspect of delayed and sustained release behaviors. Also, because the salt-forming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted.
• pharmaceutically acceptable salts are obtained by reacting a compound of Formula (I), Formula (II), or Formula (III) with an acid.
• the compound of Formula (I), Formula (II), or Formula (III) i.e. free base form
• Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid.
• Organic acids include, but are not limited to, l-hydroxy-2- naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4- acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor- 10- sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecyl sulfuric acid; ethane- l,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D);
• a compound of Formula (I), Formula (II), or Formula (III) is prepared as a chloride salt, sulfate salt, bromide salt, mesylate salt, maleate salt, citrate salt or phosphate salt.
• pharmaceutically acceptable salts are obtained by reacting a compound of Formula (I), Formula (II), or Formula (III) with a base.
• the compound of Formula (I), Formula (II), or Formula (III) is acidic and is reacted with a base.
• an acidic proton of the compound of Formula (I), Formula (II), or Formula (III) is replaced by a metal ion, e.g., lithium, sodium, potassium, magnesium, calcium, or an aluminum ion.
• compounds described herein coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine,
• compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like.
• Acceptable inorganic bases used to form salts with compounds that include an acidic proton include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like.
• the compounds provided herein are prepared as a sodium salt, calcium salt, potassium salt, magnesium salt, meglumine salt, N-methylglucamine salt or ammonium salt.
• solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms.
• sites on the organic radicals (e.g. alkyl groups, aromatic rings) of compounds of Formula (I), Formula (II), or Formula (III) are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic radicals will reduce, minimize or eliminate this metabolic pathway.
• the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, deuterium, an alkyl group, a haloalkyl group, or a deuteroalkyl group.
• the compounds described herein are labeled isotopically (e.g. with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
• Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine chlorine, iodine, phosphorus, such as, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 35 S, 18 F, 36 C1, 123 I, 124 I, 125 I, 131 1, 32 P and 33 P.
• isotopically-labeled compounds described herein for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays.
• substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.
• the compounds of Formula (I), Formula (II), or Formula (III) possess one or more stereocenters and each stereocenter exists independently in either the R or S configuration.
• the compound of Formula (I), Formula (II), or Formula (III) exists in the R configuration.
• the compound of Formula (I), Formula (II), or Formula (III) exists in the S configuration.
• the compounds presented herein include all diastereomeric, individual enantiomers, atropisomers, and epimeric forms as well as the appropriate mixtures thereof.
• the compounds and methods provided herein include all cis, trans, syn, anti,
• compounds of Formula (I), Formula (II), or Formula (III) are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds/salts, separating the diastereomers and recovering the optically pure individual enantiomers.
• resolution of individual enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein.
• diastereomers are separated by separation/resolution techniques based upon differences in solubility.
• separation of stereoisomers is performed by
• stereoisomers are obtained by stereoselective synthesis.
• compounds described herein are prepared as prodrugs.
• a “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They are, for instance, bioavailable by oral administration whereas the parent is not. Further or alternatively, the prodrug also has improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of a prodrug increases the effective water solubility.
• An example, without limitation, of a prodrug is a compound described herein, which is administered as an ester (the“prodrug”) but then is metabolically hydrolyzed to provide the active entity.
• a further example of a prodrug is a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
• a prodrug upon in vivo administration, is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound.
• a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.
• Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, N- alkyloxyacyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonate esters. See for example Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al ., Ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard, H.“Design and Application of Prodrugs” in A Textbook of Drug Design and Development, Krosgaard-Larsen and H.
• a hydroxyl group in the compounds disclosed herein is used to form a prodrug, wherein the hydroxyl group is incorporated into an acyloxyalkyl ester,
• a hydroxyl group in the compounds disclosed herein is a prodrug wherein the hydroxyl is then metabolized in vivo to provide a carboxylic acid group.
• a carboxyl group is used to provide an ester or amide (i.e. the prodrug), which is then metabolized in vivo to provide a carboxylic acid group.
• compounds described herein are prepared as alkyl ester prodrugs.
• Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound of Formula (I), Formula (II), or Formula (III) as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds is a prodrug for another derivative or active compound.
• any one of the hydroxyl group(s), amino group(s) and/or carboxylic acid group(s) are functionalized in a suitable manner to provide a prodrug moiety.
• the prodrug moiety is as described above.
• the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.
• A“metabolite” of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized.
• the term“active metabolite” refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
• the term“metabolized,” as used herein, refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound.
• cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic-acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulfhydryl groups.
• Metabolites of the compounds disclosed herein are optionally identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds.
• Ci-C x includes Ci-C 2 , C 1 -C 3 . . . Ci-C x.
• a group designated as "Ci-C 6 " indicates that there are one to six carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms.
• C 1 -C 4 alkyl indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso propyl, «-butyl, Ao-butyl, sec-butyl, and /-butyl.
• An“alkyl” group refers to an aliphatic hydrocarbon group.
• the alkyl group is branched or straight chain.
• the“alkyl” group has 1 to 10 carbon atoms, i.e. a Ci-Ci 0 alkyl.
• a numerical range such as“1 to 10” refers to each integer in the given range; e.g.,“1 to 10 carbon atoms” means that the alkyl group consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term“alkyl” where no numerical range is designated.
• an alkyl is a Ci-C 6 alkyl.
• the alkyl is methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, or t- butyl.
• Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.
• An“alkylene” group refers to a divalent alkyl radical. Any of the above mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl.
• an alkelene is a Ci-C 6 alkylene.
• an alkylene is a Ci-C 4 alkylene.
• Typical alkylene groups include, but are not limited to, -CH 2 -, - CH2CH2-, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, and the like. In some embodiments, an alkylene is -CH 2 -.
• An“alkoxy” group refers to a (alkyl)O- group, where alkyl is as defined herein.
• alkylamine refers to the -N(alkyl) x H y group, where x is 0 and y is 2, or where x is 1 and y is 1, or where x is 2 and y is 0.
• An“hydroxyalkyl” refers to an alkyl in which one hydrogen atom is replaced by a hydroxyl.
• a hydroxyalkyl is a Ci-C 4 hydroxyalkyl.
• hydroxyalkyl groups include, but are not limited to, -CH 2 OH, -CH 2 CH 2 OH, - CH 2 CH 2 CH 2 OH, -CH 2 CH 2 CH 2 CH 2 OH, and the like.
• aminoalkyl refers to an alkyl in which one hydrogen atom is replaced by an amino.
• aminoalkyl is a Ci-C 4 aminoalkyl.
• Typical aminoalkyl groups include, but are not limited to, -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , - CH 2 CH 2 CH 2 CH 2 NH 2 , and the like.
• alkenyl refers to a type of alkyl group in which at least one carbon- carbon double bond is present.
• R is H or an alkyl.
• an alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like.
• alkynyl refers to a type of alkyl group in which at least one carbon- carbon triple bond is present.
• an alkenyl group has the formula -CoC-R, wherein R refers to the remaining portions of the alkynyl group.
• R is H or an alkyl.
• an alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
• Non-limiting examples of an alkynyl group include -CoCH, - CoCCH 3 -CoCCH 2 CH 3 , -CH 2 CoCH.
• heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g ., oxygen, nitrogen (e.g. -NH-, - N(alkyl)-, sulfur, or combinations thereof.
• a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
• a heteroalkyl is a Ci- C 6 heteroalkyl.
• the term“aromatic” refers to a planar ring having a delocalized p-electron system containing 4n+2 p electrons, where n is an integer.
• the term“aromatic” includes both carbocyclic aryl (“aryl”, e.g., phenyl) and heterocyclic aryl (or“heteroaryl” or
• heteromatic groups e.g., pyridine
• the term includes monocyclic or fused-ring polycyclic ( i.e ., rings which share adjacent pairs of carbon atoms) groups.
• the term“carbocyclic” or“carbocycle” refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from“heterocyclic” rings or“heterocycles” in which the ring backbone contains at least one atom which is different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycles include aryls and cycloalkyls.
• aryl refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom.
• aryl is phenyl or a naphthyl.
• an aryl is a phenyl.
• an aryl is a phenyl, naphthyl, indanyl, indenyl, or tetrahyodronaphthyl.
• an aryl is a C 6 -C l0 aryl.
• an aryl group is a monoradical or a diradical (i.e., an arylene group).
• cycloalkyl refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom.
• cycloalkyls are spirocyclic or bridged compounds.
• cycloalkyls are optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom.
• Cycloalkyl groups include groups having from 3 to 10 ring atoms.
• cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl and bicycle[ 1.1.1 Jpentyl.
• a cycloalkyl is a C 3 -C 6 cycloalkyl.
• halo or, alternatively,“halogen” or“halide” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.
• fluoroalkyl refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom.
• a fluoralkyl is a Ci-C 6 fluoroalkyl.
• heterocycle refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings containing one to four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S and N, wherein each heterocyclic group has from 3 to 10 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms.
• Non-aromatic heterocyclic groups also known as heterocycloalkyls
• aromatic heterocyclic groups include rings having 5 to 10 atoms in its ring system.
• the heterocyclic groups include benzo-fused ring systems.
• non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1, 2,3,6- tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H
• aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinox
• a group derived from pyrrole includes both pyrrol-l-yl (A-attached) or pyrrol-3-yl (C-attached).
• a group derived from imidazole includes imidazol-l-yl or imidazol-3-yl (both A-attached) or imidazol-2-yl, imidazol-4-yl or imidazol- 5-yl (all C-attached).
• the heterocyclic groups include benzo-fused ring systems.
• at least one of the two rings of a bicyclic heterocycle is aromatic.
• both rings of a bicyclic heterocycle are aromatic.
• heteroaryl or, alternatively,“heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur.
• heteroaryl groups include monocyclic heteroaryls and bicyclcic heteroaryls.
• Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl.
• Monocyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, l,8-naphthyridine, and pteridine.
• a heteroaryl contains 0-4 N atoms in the ring.
• a heteroaryl contains 1-4 N atoms in the ring.
• a heteroaryl contains 0-4 N atoms, 0-1 0 atoms, and 0-1 S atoms in the ring.
• a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring.
• heteroaryl is a Ci-C 9 heteroaryl.
• monocyclic heteroaryl is a Ci-C 5 heteroaryl.
• monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl.
• bicyclic heteroaryl is a C 6 - Cgheteroaryl.
• A“heterocycloalkyl” group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, a heterocycloalkyl is fused with an aryl or heteroaryl.
• the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2, 5-dithionyl, pyrrolidine-2, 5-dionyl,
• heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides.
• a heterocycloalkyl is a C 2 -Cioheterocycloalkyl.
• a heterocycloalkyl is a C - C ioheterocycloalkyl.
• a heterocycloalkyl contains 0-2 N atoms in the ring.
• a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring.
• bond refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure.
• bond when a group described herein is a bond, the referenced group is absent thereby allowing a bond to be formed between the remaining identified groups.
• moiety refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
• optional substituents are independently selected from halogen, -CN, -NH 2 , -OH, -NH(CH 3 ), -N(CH 3 ) 2 , -CH 3 , - CH 2 CH 3 , -CF 3 , -OCH 3 , and -OCF 3 .
• substituted groups are substituted with one or two of the preceding groups.
• each R 21 is independently selected from Ci-C 6 alkyl, Ci-C 6 heteroalkyl, C3-C 6 cycloalkyl, C 2 - C 6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl; or two R 20 groups are taken together with the N atom to which they are attached to form a N- containing heterocycle; each R 21 is independently selected from Ci-C 6 alkyl, Ci- C 6 heteroalkyl, C3-C 6 cycloalkyl, C 2 -C 6 heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl.
• module means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.
• modulator refers to a molecule that interacts with a target either directly or indirectly.
• the interactions include, but are not limited to, the interactions of an agonist, partial agonist, an inverse agonist, antagonist, degrader, or combinations thereof.
• a modulator is an agonist.
• administer refers to the methods that may be used to enable delivery of compounds or
• compositions to the desired site of biological action include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration.
• parenteral injection including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion
• topical and rectal administration include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration.
• parenteral injection including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion
• topical and rectal administration including topical and rectal administration.
• Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein.
• the compounds and compositions described herein are administered orally.
• the terms“co-administration” or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.
• the terms“effective amount” or“therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
• an“effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms.
• An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.
• the terms“enhance” or“enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect.
• the term“enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system.
• An“enhancing- effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.
• the term“pharmaceutical combination” as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients.
• the term“fixed combination” means that the active ingredients, e.g. a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
• the term“non-fixed combination” means that the active ingredients, e.g.
• a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, and a co-agent are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient.
• cocktail therapy e.g. the administration of three or more active ingredients.
• the term“subject” or“patient” encompasses mammals.
• mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats;
• the terms“treat,”“treating” or“treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and/or therapeutically.
• the compounds described herein are formulated into pharmaceutical compositions.
• Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
• the compounds described herein are administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition.
• Administration of the compounds and compositions described herein can be effected by any method that enables delivery of the compounds to the site of action.
• enteral routes including oral, gastric or duodenal feeding tube, rectal suppository and rectal enema
• parenteral routes injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural and subcutaneous), inhalational, transdermal, transmucosal, sublingual, buccal and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route may depend upon for example the condition and disorder of the recipient.
• compounds described herein can be administered locally to the area in need of treatment, by for example, local infusion during surgery, topical application such as creams or ointments, injection, catheter, or implant.
• topical application such as creams or ointments, injection, catheter, or implant.
• the administration can also be by direct injection at the site of a diseased tissue or organ.
• compositions suitable for oral administration are presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
• the active ingredient is presented as a bolus, electuary or paste.
• compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
• the tablets are coated or scored and are formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration.
• the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
• the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings.
• concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
• Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations of active compound doses.
• compositions are formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
• Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
• the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
• compositions may be presented in unit- dose or multi -dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use.
• sterile liquid carrier for example, saline or sterile pyrogen-free water
• Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
• compositions for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
• Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
• Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
• the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
• compositions may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
• the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
• compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner.
• Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.
• compositions may be administered topically, that is by non-systemic administration. This includes the application of a compound of the present invention externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream.
• systemic administration refers to oral, intravenous, intraperitoneal and
• compositions suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
• the active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, for instance from 1% to 2% by weight of the formulation.
• compositions for administration by inhalation are conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray.
• Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
• the dosage unit may be determined by providing a valve to deliver a metered amount.
• pharmaceutical preparations may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch.
• the powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
• compositions described herein may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
• the compounds of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof are used in the preparation of medicaments for the treatment of diseases or conditions in a mammal that would benefit from modulation of somatostatin activity.
• Methods for treating any of the diseases or conditions described herein in a mammal in need of such treatment involves administration of pharmaceutical compositions that include at least one compound of Formula (I), Formula (II), or Formula (III) or a pharmaceutically acceptable salt, active metabolite, prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said mammal.
• compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments.
• the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician.
• Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.
• compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose.”
• prophylactically effective amount or dose the precise amounts also depend on the patient's state of health, weight, and the like. When used in patients, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.
• prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.
• the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.
• a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, however, the patient requires intermittent treatment on a long-term basis upon any recurrence of symptoms.
• the amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g ., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
• doses employed for adult human treatment are typically in the range of 0.01 mg-2000 mg per day.
• the desired dose is conveniently presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub-doses per day.
• the daily dosages appropriate for the compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, described herein are from about 0.01 to about 50 mg/kg per body weight.
• the daily dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime.
• the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
• Toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD 50 and the ED 50.
• the dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD 50 and ED 50.
• the data obtained from cell culture assays and animal studies are used in formulating the therapeutically effective daily dosage range and/or the therapeutically effective unit dosage amount for use in mammals, including humans.
• the daily dosage amount of the compounds described herein lies within a range of circulating concentrations that include the ED 50 with minimal toxicity.
• the daily dosage range and/or the unit dosage amount varies within this range depending upon the dosage form employed and the route of administration utilized.
• any of the aforementioned aspects are further embodiments in which the effective amount of the compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, is: (a) systemically administered to the mammal; and/or (b) administered orally to the mammal; and/or (c) intravenously administered to the mammal; and/or (d) administered by injection to the mammal; and/or (e) administered topically to the mammal; and/or (f) administered non-systemically or locally to the mammal.
• any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once a day; or (ii) the compound is administered to the mammal multiple times over the span of one day.
• any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered continuously or intermittently: as in a single dose;
• the method comprises a drug holiday, wherein the administration of the compound is temporarily suspended or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday, dosing of the compound is resumed.
• the length of the drug holiday varies from 2 days to 1 year.
• the therapeutic effectiveness of one of the compounds described herein is enhanced by administration of an adjuvant (i.e ., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).
• an adjuvant i.e ., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced.
• the benefit experienced by a patient is increased by administering one of the compounds described herein with another agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
• a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof is co-administered with a second therapeutic agent, wherein the compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.
• the overall benefit experienced by the patient is simply be additive of the two therapeutic agents or the patient experiences a synergistic benefit.
• dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated and so forth.
• the compound provided herein when co administered with one or more other therapeutic agents, is administered either simultaneously with the one or more other therapeutic agents, or sequentially.
• the multiple therapeutic agents are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills).
• the compounds described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition.
• the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms.
• a compound described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease.
• the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject.
• DMSO dimethyl sulfoxide
• NBS N-bromosuccinimide
• NMP N-M ethyl -2-pyrrol i done
• Prep-HPLC preparative high performance liquid chromatography
• RP-HPLC reverse phase high performance liquid chromatography
• SST somatostatin
• SSTR somatostatin receptor
• TEA triethylamine
• TFA trifluoroacetic acid
• TFAA trifluoroacetic anhydride
• HC1 hydrochloric acid or hydrochloride
• K 2 CO 3 potassium carbonate
• KOH potassium hydroxide
• K 3 PO 4 tripotassium phosphate
• N 2 nitrogen gas
• NH 3 ammonia
• Na 2 S0 4 sodium sulfate
• P(t-Bu) 3 tri-tert-buytlphosphine
• Pd 2 (dba) 3 tris(dibenzylideneacetone)dipalladium(0);
• Pd(PPh 3 ) 2 Cl 2 bis(triphenylphosphine)palladium(II) dichloride
• Pd(dppf)Cl 2 [1, T-bis(diphenylphosphino)ferrocene]palladium(II) dichloride;
• Zn(CN) 2 zinc cyanide.
• Step 1-1 preparation of 5-bromo-l-fluoro-3-methoxy-2 -nitrobenzene: a mixture of 5-bromo-l,3-difluoro-2-nitrobenzene (10.0 g, 42.0 mmol, 1.0 equiv), KOH (3.1 g, 55.3 mmol, 1.3 equiv) in methanol (100 ml) was stirred at 40°C for 3 hrs, then diluted with water (200 ml). The mixture was extracted with ethyl acetate (3 x 200 ml). The combined organic solution was washed with brine, dried and concentrated to yield the title compound (11.0 g) as a crude product.
• 1HNMR 300 MHz, DMSO-d 6 ): S, 7.59 (d, 1H), 7.56 (s, 1H), 3.98 (s, 3H)
• Step 1-3 preparation of 5-bromo-3-methoxybenzene-T2-diamine: a mixture of 5- bromo-3-methoxy-2-nitroaniline (10 g, 40.5 mmol, 1.0 equiv), NH 4 Cl (10.8 g, 201.9 mmol, 5.0 equiv), ethanol (100 ml) , water (10 ml) and Fe power (11.4 g, 5.0 equiv) was stirred at 70°C for 3 hrs. After cooling to rt, the mixture was diluted with ethyl acetate (200 ml) and the solid was then filtered out. The mixture was then further diluted with water (200 ml).
• Step 1-4 preparation of tert-butyl N-rl-(2-amino-5-bromo-3-formylpyridin-4- vDpiperidin-4-vncarbamate: a mixture of 2-amino-5-bromo-4-chloropyridine-3-carbaldehyde (25.0 g, 106.2 mmol, 1.0 equiv), tert-butyl N-(piperidin-4-yl)carbamate (21.2 g, 105.9 mmol, 1.0 equiv), TEA (32.1 g, 317.2 mmol, 3.0 equiv), N,N-dimethylformamide (120 mL) was stirred for 2 hrs at 80 °C.
• Step 1-5 preparation of tert-butyl N-( l-r2-amino-5-(3-fluoro-5-methylphenvD-3- formylpyridin-4-vnpiperidin-4-yl
• Step 1-6 preparation of tert-butyl N-( l-r2-amino-3-(6-bromo-4-methoxy-lH-L3- benzodiazol-2-vD-5-(3-fluoro-5-methylphenvDpyridin-4-vnpiperidin-4-yl
• Step 1-7 preparation of tert-butyl N- 1 -r2-amino-3-(6-cvano-4-m ethoxy- 1H- 1.3-
• carbamate to each of total four microwave tubes, purged and maintained under an inert atmosphere of N 2 , tert- butyl N- ⁇ 1 - [2-amino-3 -(6-bromo-4-m ethoxy- 1 H- 1 , 3 -benzodiazol-2-yl)-5 -(3 -fluoro-5 - methylphenyl)pyridin-4-yl]piperidin-4-yl ⁇ carbamate (1.1 g, 1.7 mmol), Zn(CN) 2 (600 mg,
• Step 1-8 preparation of 2-r2-amino-4-(4-aminopiperidin-l-v0-5-(3-fluoro-5- methylphenvDpyridin-3-vn-4-methoxy-lH-E3-benzodiazole-6-carbonitrile: a mixture of tert- butyl N- ⁇ 1 - [2-amino-3 -(6-cy ano-4-m ethoxy- 1 H- 1 , 3 -benzodiazol-2-yl)-5 -(3 -fluoro-5 - methylphenyl)pyridin-4-yl]piperidin-4-yl ⁇ carbamate (80 mg, 0.14 mmol) and trifluoroacetic acid (1 mL) in dichlorom ethane (2 mL) was stirred for 2 hrs at rt and then concentrated , The crude product was purified by Prep-HPLC according to the following conditions (XBridge Prep C18): Column, 30 XBridge Pre
• Step 2-1 preparation of tert-butyl N-rl-(2-chloro-3-formylpyridin-4-vDpiperidin-4- yllcarbamate: into a 40-mL round-bottom flask, was placed 2,4-dichloropyridine-3- carbaldehyde (2.0 g, 11.36 mmol, 1.0 equiv), tert-butyl N-(piperidin-4-yl)carbamate (2.3 g, 11.48 mmol, 1.0 equiv), TEA (3.5 g, 34.59 mmol, 3.0 equiv), N,N-dimethylformamide (10 mL).
• Step 2-2 preparation of tert-butyl N-f l-r2-(dimethylamino)-3-formylpyridin-4- yllpiperidin-4-yllcarbamate: into a 40-mL sealed tube, was placed tert-butyl N-[l-(2-chloro- 3-formylpyridin-4-yl)piperidin-4-yl]carbamate (700 mg, 2.06 mmol, 1.0 equiv),
• Step 2-3 preparation of tert-butyl N-f l-r5-bromo-2-(dimethylamino)-3- formylpyridin-4-vnpiperidin-4- to tert-butyl N- ⁇ l-[2-(dimethylamino)-3- formylpyridin-4-yl]piperidin-4-yl ⁇ carbamate (600 mg, 1.72 mmol, 1.0 equiv) in DCM (10 ml), NBS (306 mg, 1.72 mmol, 1.0 equiv) was added. The mixture was then stirred at 80°C for 20 min. It was then cooled to rt, concentrated and purified by silica gel column
• Step 2-4 preparation of tert-butyl N-rl-r2-(dimethylamino)-5-(3-fluoro-5- methylphenyl
• Step 2-5 preparation of tert-butyl N-i l -r3-(6-bromo-4-methoxy- l H- 1.3- benzodiazol-2-v0-2-(dimethylamino)-5-(3-fluoro-5-methylphenv0pyridin-4-yllpiperidin-4- yl !carbamate
• tert-butyl N-[l-[2-(dimethylamino)-5-(3- fluoro-5-methylphenyl ⁇ -3-formylpyridin-4-yl]piperidin-4-yl]carbamate 150 mg, 0.33 mol
• 5-bromo-3-methoxybenzene-l, 2-diamine 142 mg, 0.65 mmol, 2.0 equiv
• NMP (2 ml)
• Na 2 S 2 0 5 125 mg, 2.0 equiv).
• Step 2-6 preparation of tert-butyl N-i l -r3-(6-cvano-4-methoxy- l H- 1.3- benzodiazol-2-v0-2-(dimethylamino)-5-(3-fluoro-5-methylphenv0pyridin-4-yllpiperidin-4- yl I carbamate: into a l0-mL microwave tube purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl N- ⁇ l-[3-(6-bromo-4-methoxy-lH-l,3-benzodiazol-2-yl)-2- (dimethylamino)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl]piperidin-4-yl ⁇ carbamate (150 mg, 0.23 mmol), Xantphos (30 mg, 0.05 mmol.
• Step 3-1 preparation of tert-butyl N-rl-(5-bromo-2-chloro-3-formylpyridin-4- vDpiperidin-4-vncarbamate: a mixture of tert-butyl N-[l-(2-chloro-3 -formylpyridin-4- yl)piperidin-4-yl]carbamate (500 mg, 1.47 mmol, Step 2-1) and NBS (290 mg, 1.63 mmol,
• Step 3-2 preparation of tert-butyl N-rl-r2-chloro-5-(3-fluoro-5-methylphenvD-3- formylpyridin-4-vnpiperidin-4-vncarbamate: Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl N-[l-(5-bromo-2- chloro-3-formylpyridin-4-yl)piperidin-4-yl]carbamate (250 mg, 0.60 mmol), (3-fluoro-5- methylphenyl)boronic acid (92 mg, 0.60 mmol, 1.0 equiv), Pd(dppf)Cl 2 (50 mg, 0.07 mmol, 0.12 equiv ), K 2 C0 3 (165 mg, 1.2 mmol, 2.0 equiv), dioxane (5 mL), H 2 0 (0.5 mL).
• Step 3-3 preparation of tert-butyl N- 1 -r2-chloro-3-(6-fluoro-4-methoxy- l H- l .3-
• Step 3-4 preparation of methyl 4-(4-(r(tert-butoxy) l-
• Step 3-5 preparation of tert-butyl N- l-r2-carbamoyl-3-(6-fluoro-4-methoxy-lH-
• Step 3-6 preparation of tert-butyl N-( l-r2-cvano-3-(6-fluoro-4-methoxy-lH-L3- benzodiazol-2-vD-5-(3-fluoro-5-methylphenvDpyridin-4-vnpiperidin-4-yl
• Step 3-7 preparation of 4-( ' 4-aminopiperidin- 1 -yl )-3-(6-f1uoro-4-methoxy- l H- l .3- benzodiazol-2-vO-5-(3-fluoro-5-methylphenvOpyridine-2-carbonitrile: into a lOO-mL round- bottom flask, was placed yield tert-butyl N- ⁇ l-[2-cyano-3-(6-fluoro-4-methoxy-lH-l,3- benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl]piperidin-4-yl ⁇ carbamate (10 mg, 0.02 mmol), DCM (5 mL), TFA (1 mL).
• Step 4-1 Preparation of 4-(4-aminopiperidin-l-yl)-3-(6-fluoro-4-methoxy-lH-l,3- benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridine-2-carboxamide: a mixture of tert- butyl N- ⁇ l-[2-carbamoyl-3-(6-fluoro-4-methoxy-lH-l,3-benzodiazol-2-yl)-5-(3-fluoro-5- methylphenyl)pyridin-4-yl]piperidin-4-yl ⁇ carbamate (20 mg, 0.04 mmol, Step 3-5), DCM (5 mL) and TFA (1 mL) was stirred for 2 hrs at rt and concentrated.
• Step 6-2 preparation of benzyl (4aS.8aS) 6-(2-amino-5-bromo-3-formyl-pyridin- 4-yl )-octahvdro-pyridor3.4-bir i .41oxazine- l -carboxyl ate: into a lOO-mL round-bottom flask, was placed 2-amino-5-bromo-4-chloropyridine-3-carbaldehyde (2 g, 8.5 mmol, 1.5 equiv), benzyl (4aS,8aS)-octahydro-lH-pyrido[3,4-b]morpholine-l-carboxylate (1.57 g, 5.7 mmol, 1.0 equiv), TEA (1.72 g, 17.00 mmol, 3.0 equiv), N,N-dimethylformamide (20 mL).
• Step 6-3 preparation of benzyl (4aS.8aS)-6-r2-amino-5-(3-fluoro-5- methyl phenyl )-3-formylpyridin-4-yl1-octahvdro- l H-pyridor3.4-b1morpholine- l -carboxyl ate: into a 50-mL 3-necked round-bottom flask purged and maintained with nitrogen, was placed benzyl (4aS,8aS)-6-(2-amino-5-bromo-3-formylpyridin-4-yl)-octahydro-lH-pyrido[3,4- b]morpholine-l-carboxylate (300 mg, 0.63 mmol, 1.0 equiv), (3-fluoro-5- methylphenyl)boronic acid (192 mg, 1.25 mmol, 2.0 equiv), Pd 2 (dba)3.CHCl
• Step 6-4 preparation of benzyl (4aS.8aS)-6-r2-amino-3-(6-bromo-4-methoxy- l H- 1.3-benzodiazol-2-yl )-5-(3-fluoro-5-methylphenyl )pyridin-4-yl1-octahvdro-l H-
• Step 6-5 preparation of benzyl -6-r2-amino-3-(6-cvano-4-methoxy-lH-
• Step 6-6 preparation of 2-[4-[(4aS, 8aS)-octahydro-lH-pyrido[3,4-b]morpholin-6-yl]-2- amino-5-(3-fluoro-5-methylphenyl)pyri din-3 -yl]-4-methoxy-lH-l, 3-benzodiazole-6- carbonitrile:a mixture of benzyl (4aS, 8aS)-6-[2-amino-3-(6-cyano-4-methoxy-lH-l,3- benzodiazol-2-yl)-5-(3-fluoro-5-methylphenyl)pyridin-4-yl]-octahydro-lH-pyrido[3,4- b]morpholine-l-carboxylate (70 mg, 0.11 mmol, 1.00 equiv), trifluoroacetic acid (2 mL) was stirred for 3 hrs at 60 °C.
• Example A-l Parenteral Pharmaceutical Composition
• a parenteral pharmaceutical composition suitable for administration by injection (subcutaneous, intravenous)
• 1-100 mg of a water-soluble salt of a compound Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt or solvate thereof is dissolved in sterile water and then mixed with 10 mL of 0.9% sterile saline.
• a suitable buffer is optionally added as well as optional acid or base to adjust the pH.
• the mixture is incorporated into a dosage unit form suitable for administration by injection
• a sufficient amount of a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof is added to water (with optional solubilizer(s), optional buffer(s) and taste masking excipients) to provide a 20 mg/mL solution.
• a tablet is prepared by mixing 20-50% by weight of a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, 20-50% by weight of microcrystalline cellulose, 1-10% by weight of low-substituted hydroxypropyl cellulose, and 1-10% by weight of magnesium stearate or other appropriate excipients. Tablets are prepared by direct compression. The total weight of the compressed tablets is maintained at 100 -500 mg.
• a pharmaceutical composition for oral delivery 10-500 mg of a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof, is mixed with starch or other suitable powder blend. The mixture is incorporated into an oral dosage unit such as a hard gelatin capsule, which is suitable for oral administration.
• 10-500 mg of a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof is placed into Size 4 capsule, or size 1 capsule (hypromellose or hard gelatin) and the capsule is closed.
• Example A-5 Topical Gel Composition
• a compound of Formula (I), Formula (II), or Formula (III), or a pharmaceutically acceptable salt thereof is mixed with hydroxypropyl celluose, propylene glycol, isopropyl myristate and purified alcohol USP.
• the resulting gel mixture is then incorporated into containers, such as tubes, which are suitable for topical administration.
• Crude membrane fractions are prepared from Chinese hamster ovary (CHO) cells stably expressing one of the five human or rodent somatostatin receptor subtypes.
• the cells are grown to 85 - 100% confluence on standard tissue culture dishes in DM-MEM growth media (Gibco) with following additives: 10% fetal bovine serum (Gibco), 100 U/mL penicillin (Gibco), 100 ug/mL streptomycin (Gibco), 10 mM HEPES (Gibco), 0.5 mg/mL G- 418 (Gibco).
• the cells are centrifuged at 43,500 x g, homogenized, and the resulting membranes are collected by centrifugation at 67,000 x g.
• the membranes are then resuspended in binding buffer containing the protease inhibitor cocktail using a glass dounce homogenizer.
• GPCRs Gi coupled G-protein coupled receptors
• cAMP intracellular cyclic AMP
• the cells are cultured at 37 °C, 5% C0 2 and 95% humidity. On the day of the assay, the media is aspirated and the cells are treated with 50 pL of 1.6 pM NKH477 (Sigma #N3290) plus various dilutions of compounds of the invention in assay buffer [lx Hank's Balanced Salt Solution (ThermoFisher
• the cells are incubated for 20 minutes at 37 °C (the final concentration of the compounds of the invention are typically 0 - 10,000 nM).
• the cells are treated with 50 pL of lysis buffer (HRTF cAMP kit, Cisbio).
• HRTF cAMP kit HRTF cAMP kit, Cisbio
• the lysate is transferred to 384-well plates and cAMP detection and visualization antibodies are added and incubated for 1-24 hours at room temperature.
• the time-resolved fluorescent signal is read with a Tecan MlOOOPro multiplate reader.
• the intracellular cAMP concentrations are calculated by regression to a standard curve and are plotted vs. the concentration of the compounds of the invention and the EC50 of the compounds are calculated using standard methods. All data manipulations are in GraphPad Prism v6.
• A EC50 ⁇ 0.1 nM
• B EC50 between >0.1 nM and ⁇ 1 nM
• C EC50 >1 nM
• the in vitro stabilities of compounds of interest were determined for various species using pooled male and female human, pooled male Sprague-Dawley rat, pooled male Cynomolgus monkey, and pooled male Beagle dog liver microsomes at microsomal protein concentrations of 0.5 mg/mL. Incubations were carried out in a potassium phosphate buffer (50 mM).
• the NADPH-generating system was composed of NADP+ (1 mM), magnesium chloride (3 mM), EDTA (1 mM), glucose-6-phosphate (5 mM) and glucose-6-phosphate dehydrogenase (1 Unit/mL) for all experiments.
• Table D illustrates human liver microsomal stability of exemplary compounds.

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• 2019
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• 2020
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• 2021
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• 2022
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